The human genome is replete with the remnants of transposition that have accumulated throughout the mammalian radiation, and is ongoing in human populations today. These sequences comprise ~50% of human DNA, but the impact that transposable elements and other repetitive DNAs have on our genome remain poorly understood. How the genome contends with repetitive DNA is key to our improved understanding of genome biology as well as understanding disease processes in constitutional and somatic disorders. To investigate these questions requires thorough understanding not only of repetitive DNA, but also how these sequences impact our ability to capture genomic information from current sequencing technologies and methodologies. The goal of my research is to reveal the impacts of homologous sequences on mammalian genomes and the mechanisms that guide genomic instability fostered by repeat sequences. For the next 5 years, I will primarily focus on determining the prevalence of repetitive sequence-mediated genomic instability and the mechanisms driving this instability in mammalian genomes. I hypothesize that repeats play an important role in fostering genomic rearrangements that can lead to disease and variation in the population. To study this process, we will examine the prevalence of transposable element-mediated rearrangements in human and mouse genomes and investigate the ability of various sequencing methodologies and calling algorithms to identify these events. We will apply our knowledge to somatic tandem duplications, and infer mechanisms of junction formation in the generation of these events. We seek to identify key mechanistic features of the genomic rearrangements found to be mediated by repeats, and will also examine genes that control ectopic recombination between repeats. Finally, to extend our models of this instability and to develop a more comprehensive view of the impact of transposons on genes in which they reside, we will examine the role of transposable elements in genome folding and in alternative splicing. Successful completion of these investigations will greatly increase the existing knowledge of repeat-mediated rearrangements in mammalian genomes, and will expand our understanding of how repeats influence genome biology.